Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome

We show that haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes.     

A Novel Credit Rating Migration Modeling Approach Using Macroeconomic Indicators

Modeling credit rating migrations conditional on macroeconomic conditions allows financial institutions to assess, analyze, and manage the risk related to a credit portfolio. Existing methodologies to model credit rating migrations conditional on the business cycle suffer from poor accuracy, difficult readability, or model inconsistencies. The modeling methodology proposed in this paper extends ordinal logistic regression to estimate the complete migration matrix including default rates as a function of rating dynamics and macroeconomic indicators. The gradient and Hessian derivations show efficient optimization within the Levenberg–Marquardt algorithm. The proposed modeling methodology is applied to model corporate rating migrations using historical data from 1984 to 2011. It is shown that the resulting model captures the cyclical behavior of credit rating migrations and default rates, and is able to approximate historic migration levels with good precision. The model therefore permits analysis of the impact of economical downturn conditions on a credit portfolio. Copyright © 2013 John Wiley & Sons, Ltd.     

Geometry sensing by dendritic cells dictates spatial organization and PGE2-induced dissolution of podosomes

Assembly and disassembly of adhesion structures such as focal adhesions (FAs) and podosomes regulate cell adhesion and differentiation. On antigen-presenting dendritic cells (DCs), acquisition of a migratory and immunostimulatory phenotype depends on podosome dissolution by prostaglandin E(2) (PGE(2)). Whereas the effects of physico-chemical and topographical cues have been extensively studied on FAs, little is known about how podosomes respond to these signals. Here, we show that, unlike for FAs, podosome formation is not controlled by substrate physico-chemical properties. We demonstrate that cell adhesion is the only prerequisite for podosome formation and that substrate availability dictates podosome density. Interestingly, we show that DCs sense 3-dimensional (3-D) geometry by aligning podosomes along the edges of 3-D micropatterned surfaces. Finally, whereas on a 2-dimensional (2-D) surface PGE(2) causes a rapid increase in activated RhoA levels leading to fast podosome dissolution, 3-D geometric cues prevent PGE(2)-mediated RhoA activation resulting in impaired podosome dissolution even after prolonged stimulation. Our findings indicate that 2-D and 3-D geometric cues control the spatial organization of podosomes. More importantly, our studies demonstrate the importance of substrate dimensionality in regulating podosome dissolution and suggest that substrate dimensionality plays an important role in controlling DC activation, a key process in initiating immune responses.     

Study on Pollution Cost Control Model under Asymmetric Information Based on Principal Agent

Pollution cost control is key to solve pollution problem. The paper takes pollution control cost of pollution control contract between management authority and pollutant discharge enterprise as research object, considers pollution control quality level, pollution control quality inspection and pollution control cost model, and establishes pollution control cost model of management authority and pollutant discharge enterprise, including rational constraints of pollutant discharge enterprise. And it analyzes principal-agent relationship between the two under condition of asymmetric information, and un-observability of pollution control level is shown as hiding information of sewage enterprises. In essence, it is problem of adverse selection in principal-agent. Pollution control cost of management is objective function. The first order condition of pollution control cost of sewage enterprise is transformed into state space equation, and optimal control of problem is solved by using maximum principle. In particular, management authority, as principal, uses pollution control provisions to reward, punish and encourage pollutant discharge enterprises as agents.     

Telomeres and telomerase as targets for cancer therapy

Telomeres are protective structures located at the ends of all eukaryotic chromosomes. Telomere shortening upon cell division restricts the proliferative capacity of most normal human cells due to the lack of telomerase, an enzyme synthesizing telomeric DNA de novo. Since most tumor cells are reliant on the activity of telomerase to maintain the stability of predominantly short individual telomeres, inhibition of this enzyme presents an attractive approach for a mechanism-based anticancer therapy. Here, we review advances and obstacles in targeting telomerase and telomeres and discuss potential applications of such approaches for the clinic. Received 9 November 2006; received after revision 8 December 2006; accepted 17 January 2007